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Osteonecrosis. What Is New?
Review Article
Osteonecrosis. What Is New? M. Ángeles Martínez-Ferrer, Pilar Peris, and Núria Guañabens Servicio de Reumatología, Hospital Clínic, Barcelona, Spain
Osteonecrosis, also known as aseptic necrosis, is a pathological process that has been associated with numerous conditions. The pathogenesis of osteonecrosis and especially the treatment both remain an area of controversy. In this article we review the etiology and pathogenesis of osteonecrosis as well as the main therapeutic options.
head is the zone most frequently affected and the one in which there is the most experience regarding evolution and treatment; therefore, in this article, we will be referring especially to that localization.
Key words: Osteonecrosis. Avascular necrosis. Aseptic
Thought he true incidence of this process is not known, it is estimated that approximately 15 000 new cases present themselves each year in the United States, constituting 10% of the yearly 500 000 arthroplasties done every year in that country, with a male:female ratio of 8:1.1 Because non-traumatic hip ON in its early stages is frequently asymptomatic, it is difficult to establish the natural history of this process. In spite of that, 68%80% of patients with asymptomatic hip ON without treatment progress to the final stages of ON in 3 to 5 years, without any relationship to etiology and the time of evolution to collapse. 31%-35% will have a satisfactory evolution without surgery2; nonetheless, up to 50% of the cases require arthroplasty at 3 years since diagnosis and between 30%-70% of cases has bilateral affection of the hips.3 Advance stages at the moment of diagnosis, the extension of the lesion (>50% of the femoral head) and its localization (anterolateral zone of the femoral head) are poor prognostic factors. The femoral head is the most frequent localization, but other sites can be affected also, among which the humeral head, the condyle of the femur, the proximal tibia and the carpal and tarsal bones deserve mention. Around 3% of patients present multifocal ON.1
necrosis. Ischemic necrosis.
Osteonecrosis. ¿Qué hay de nuevo? La osteonecrosis, también conocida como necrosis avascular, se ha asociado a numerosos procesos. Su patogenia y, especialmente, su tratamiento son motivo de controversia. En este artículo se revisan la etiología y la patogenia de la osteonecrosis y sus principales opciones terapéuticas. Palabras clave: Osteonecrosis. Necrosis avascular.
Necrosis aséptica. Necrosis isquémica.
Osteonecrosis (ON), also known as avascular necrosis or aseptic necrosis, is a disease that has been related to multiple processes. Though in many cases the mechanisms that lead to ON are not completely clear, in others a deterioration of the vascularization of bone that produces necrosis of the bone tissue has been identified. It is a progressive process that can lead to fragmentation and sinking of the bone structure and to joint destruction secondarily, in a period of 3 to 5 years. Because ON affects mainly young adults between 20 and 40 years of age, its consequences are a real public health problem. The most frequent localization is the epiphysis and, although any part of the skeleton is liable to undergo ON, the femoral
Correspondence: Dra. M.A. Martínez-Ferrer. Servicio de Reumatología. Hospital Clínic. Villarroel, 170. 08036 Barcelona. España. E-mail: [email protected] Manuscript received January 18, 2006; accepted for publication June 7, 2006.
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Epidemiology and Evolution
Etiology Several causes associated to the development of ON have been described. In some, such as in proximal femur fracture, sickle cell anemia, or decompression illness, the cause seems evident, while in others, such as treatment with glucocorticoids (GC) or alcohol consumption, the cause is not so clear. The common denominator is the femoral head liability to ischemia, but the pathogenic mechanism is variable. In the case of a femoral fracture, compression or rupture of a blood vessel is the cause of ON, while in sickle cell anemia and in decompression illness, it is attributed to alterations in sinusoidal circulation. Several pathogenic mechanisms have been
Martínez-Ferrer MA et al. Osteonecrosis. What Is New?
proposed in relation to the rest of the ON, such as vascular alterations secondary to atherosclerosis, coagulation defects, repeated microfractures, fat embolism, adypocyte hypertrophy, among others. For example, with respect to GC it has been described that the alterations in the metabolism of lipids associated to this treatment would favor the development of fat embolisms that would lead to micro vessel obstruction or would produce an increase in bone marrow fat that would lead to vascular insufficiency due to compression, leading to the development of ON. On the other hand, treatment with GC has also been associated to an increment in the production of endothelium vasoconstrictive substances such as endothelin 1, which could lower the tissue perfusion and favor the appearance of this complication.4 Thrombophilia and hypofibrinolysis have also been implicated in the development of ON in some cases, causing intravascular coagulation in the bone tissue microcirculation that leads to venous or arterial thrombosis.4 Osteocyte and osteoblast apoptosis has been pointed out in the past few years as an important probable ethiopathogenic mechanism in this disease, concretely in relationship to ON due to GC and alcohol, signaling that it may be mediated, at least partially, by an increase in the local production of nitric oxide.5 In patients with ON due to GC, an abundance of apoptotic osteocytes that affect the adjacent lining cells in the area of bone collapse have been observed. It has been proposed that this fact would lead to further bone collapse.6,7 Therefore, osteocyte apoptosis seems to play a fundamental role in the local activation of osteoclasts to initiate bone resorption.8 There has been several cases described recently of familial dominant autosomic ON linked to mutations in the collagen type II (COL2A1) gene.9 Though this mutation constitutes an infrequent cause of ON, because it has not been observed in patients with idiopathic ON without a family history, it implicates the functional alterations of type II collagen in the development of some cases of ON.
Frequent Causes of Osteonecrosis Besides posttraumatic ON, be it due to femoral neck fracture (especially the sub capital fractures) or hip luxation (especially if reduction is performed late rather than early), treatment with GC is one of the most common causes of ON. Between 3% and 25% of patients using GC develop ON,1 with a dose dependent risk. In this sense, the use of moderate doses of GC (<15-20 mg/day) are associated with a low risk of ON (<3%), while larger doses used for longer periods of time confer a higher risk.10 Nonetheless, one must remember that these patients frequently have multiple associated risk factors that can lead to the development of this process. Some studies indicate that 100% of the cases of ON associated to GC treatment had continued treatment with prednisone in excess of 20
mg/day.10 There is evident that points out that the initial dose of GC can be as important as the total dose and the duration of treatment. In transplant patients, the development of ON is a relatively frequent complication, with prevalence oscillating between 2% and 24% and depends on the dose employed and the transplanted organ.11 The incidence of ON tends to be lower, in the order of 2%-3%, after liver or heart transplant than after lung or kidney transplant, where incidence is around 10% and 34%.14,15 In these patients, a history of osteopenia and hyperparathyroidism are risk factors that have been associated to the risk of ON.16 Frequently ON in renal transplant patients can affect more than one localization (50%-70% of cases).17,18 Nonetheless, its incidence has lowered since the introduction of new immunosupressants such as tacrolimus, allowing for a reduction in the dose of GC.19 Bone marrow transplant (BMT) has also been associated to this complication, especially allogenic BMT, with a frequency around 5%20,21; graft-versus-host disease and the cumulative dose of GC are risk factors related to the development of ON in these patients.22 But other factors such as the type of hematologic disease and the gender, both of the patient and the donor, have also been related to this complication. Thus the patients with acute lymphoblastic leukemia and women who have received a transplant from another woman, present ON with a greater frequency.23 In other diseases such as systemic lupus erythematosus (SLE), the development of ON has been observed in 4% of patients24,25; but if treatment with GC, especially at a dose >20 mg/day, constitutes one of the main risk factors for the development of ON in these patients,26-28 dyslipidemia, and antiphospholipid antibodies are other factors relating to the development of ON in this process.29 Though the role of antiphospholipid antibodies in the development of ON in patients with SLE is controverted,3034 their relationship with the development of ON in patients with primary antiphospholipid síndrome seems evident. Thus, it has been recently shown that 20% of these patients develop ON.35 Some studies, though not all, have also observed an increment in the incidence of antiphospholipid antibodies in patients with ON.29,36,37 Isolated cases of patients with multifocal ON and associated antiphospholipid antibodies have been described.38-40 Other isolated studies implicate alterations in other coagulation factors with relation to the development of ON, such as the presence of a mutation in the factor V Leiden gene41,42 or the inhibition of plasminogen activation factor.43 The excessive consumption of alcohol is also a frequent cause of ON. Even though the mechanism by which this complication is produced in these patients, several ethiopathogenic mechanisms have been proposed in relation to the development of ON in this process, such as fat embolus, venous stasis or the increase in the concentrations of cortisol, among others. The Reumatol Clin. 2007;3(2):78-84
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development of ON is frequent in other diseases such as sickle cell anemia, in which up to 50% of patients can present the complication, and in Gauchers´ disease, a metabolic entity in which approximately 60% of patients develop ON. Lastly, human immunodeficiency virus (HIV), independent of the degree of immune system compromise, can produce an increment in the risk of ON; in these patients a prevalence of up to 4% has been noted, occasionally presenting as multifocal ON. Factors such as dyslipidemia secondary to the treatment of protease inhibitors, GC treatment, hypolipemics or testosterone could be related to its development.44 The role that the complications linked to HIV, mainly coagulation disorders (antiphospholipid antibodies or S protein deficit) and vasculitis have been a motive of discussion but their participation has not been able to be confirmed. It is probable that in these patients the development of ON is multifactorial.45,46 A recent study that analyzes the factors related to ON in patients with HIV indicate that the majority of patients (86%) had at least one known risk factor for this complication.47
cuts. Bone scanning is a less sensitive and specific technique than RM in early stages, though it is useful in the diagnosis of multifocal illness. Another imaging technique is computed tomography (CT) that can be useful in the detection of an occult subchondral fracture, but is less sensitive in the early diagnosis of ON (stage I). As with MR, CT is not necessary for the diagnosis of ON in late stages of disease because diagnosis with simple x-rays is easy.
Classification and Staging of Osteonecrosis Several staging indexes for ON based on the degree of x-ray affection, histological damage, and clinical symptoms have been proposed. The classification of Ficat et al48 stands out among them, basing itself on the x-ray findings and has been used extensively (Table 1), as does the index of the Association for the Research of Circulation of the Bone (ARCO), 49 that unifies the results of several classifications (Table 2). The latter is difficult to apply in daily practice and is mainly employed in research studies.
Diagnosis Treatment Upon suspicion of ON, a simple x-ray study must be carried out. When the x-ray is normal and there is a clinically based suspicion of ON, the imaging method of choice is magnetic resonance (MR). At the beginning of symptoms, the radiological studies tend to be normal; the first findings are changers in the bone mineral density followed by sclerosis and the appearance of cysts as the disease progresses. The pathognomonic sign is the “halfmoon” image, indicating subchondral collapse. In advance stages of the disease there is an objective loss of sphericity of the femoral head and a narrowing of the joint space as well as degenerative changes of the acetabulum. Both hips should always be x-rayed to evaluate bilateral affection. MR constitutes the most sensitive technique for diagnosis of ON and allows for its diagnosis in early stages of disease. The study must include imaging in T1 and T2 with coronal and sagital
A controversial topic in ON is, without a doubt, its therapeutic approach. Thus, in many occasions, conservative treatment is indicated for this process, including joint rest and analgesia. Nonetheless, this type of treatment does not seem to modify the natural evolution of ON nor prevent bone collapse, because with this kind of treatment, only 23% of hips present a good clinical result after a mean follow up of 34 months.50 Central decompression by single or multiple perforations (forage) through the femoral neck is another kind of treatment that has frequently been used. It a surgical procedure in which several perforations of a small caliber or a larger one are done attaining decompression at the same time the necrotic bone tissue is removed. When the intraosseus pressure diminishes, pain is relieved and, theoretically, revascularization of the necrotic tissue
TABLE 1. ON Classification According to Ficat et al48 Stage 0
Diagnosis techniques are normal and patient is asymptomatic
Stage 1
Normal x-ray, asymptomatic or, mild symptoms, bone scan shows a cold spot on the femoral head and biopsy is positive
Stage 2
x-ray changes, mild symptoms, and increased uptake on bone scan. According to x-ray affection it can be classified into A or B
Stage 3
x-ray changes, loss of sphericity and collapse, mild to moderate symptoms, increase in bone uptake
Stage 4
x-ray changes, joint space narrowing and acetabulum changes, moderate to severe symptoms and increased uptake in bone scan
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Martínez-Ferrer MA et al. Osteonecrosis. What Is New?
TABLE 2. Osteonecrosis Classification According to ARCO49,* Stage 0
The diagnostic tests are normal, patients are asymptomatic, diagnosis is histological
Stage 1
Normal x-ray and CT, MR and biopsy are negative. According to the extension of the lesion it is subclassified in: A: <15% B: 15%-30% C: >30%
Stage 2
Radiographic changes without collapse. According to the degree of affection it is sub classified in A, B, or C
Stage 3
“Half moon” sign is characteristic; indicating collapse. MR or CT can be necessary for diagnosis. The extension of the lesion is sub classified in A, B, or C
Stage 4
There is a flattening of the femoral head with joint space narrowing and early signs of arthrosis. Collapse usually occurs in the anterolateral or superior loading area. The best technique to observe collapse is CT. This stage can be subdivided in: A: extension of the collapse <15% and 2 mm depression B: collapse 15%-30%, depression 2-4 mm C: collapse >30%, depression >4 mm
Stage 5
All of the abovementioned radiographic changes and a narrowing of the joint space. Collapse secondary to arthrosis, sclerosis, cysts, and marginal osteophytes
Stage 6
Extensive destruction of the femoral head
*MR indicates magnetic resonance; CT, computerized tomography.
occurs. In the last few years there have been numerous studies attempting to evaluate the efficacy of this technique.51 For example, in a randomized study that compared the efficacy of this technique versus conservative treatment the results showed that, even if there were significant differences in favor of treatment with decompression in relation to the improvement of pain, no differences were observed regarding radiographic evolution,52 while a meta-analysis comparing the efficacy of both procedures indicated that the forage could only be useful in the treatment of stage I hip ON53; therefore this type of treatment is indicated in patients presenting early stages of disease and limited extension lesions.54,55 Recently it has been pointed out that additional treatment with local growth factors such as morphogenetic protein could improve this treatments efficacy. 56,57 Another surgical procedure cited frequently is femoral neck osteotomy, consisting in the modification of the loading axis on the femoral head. This procedure would facilitate recovery by modifying the load over the necrotic lesion. But the results of clinical trials are variable and, curiously, the best results are observed in Japanese populations where, after a follow up period of 2-9 years, patients show excellent results of up to 90%.58 This procedure is currently being abandoned. There are other techniques that also imply a surgical approach of the bone lesion, such as the cortical-spongy bone implant and the revascularized bone implant. In the former a cortical or spongy bone implant (autologous or allogenic) is introduced through the decompression zone into the necrotic area after debridement. The bone implant offers structural support for the subchondral bone, theoretically preventing bone collapse. Marcus et al59 described the results of this technique in a group of
48 patients with different stages of affection (I-IV). Therefore, while 64% of the patients in stages I and II presented a good evolution with this type of treatment, no patient I stages III and IV had satisfactory results. Another technique that has been employed is the impacted bone implant, with interesting results in extensive ON. 60 On the other hand, the implant of vascularized free or pediculated bone consists in the implantation of cortical or spongy bone tissue with its vascular appendage (usually free peroneus through microsurgery) to the interior of the femoral neck through a decompression tract. The results described with this type of implant are better.61 In a study that included 101 hips (in all stages of ON) from 86 patients and with a minimum follow-up of 5 years, there was a hip survival of 61% at 5 years.62 It must be said that a recent technique has been applied to this disease, the implantation of a tantalium rod or screw, that consists in the collocation of a porous bar made tantalium in the interior of the femoral neck (Figure); its indication is based on the fact that it will serve as mechanical support and the intrinsic properties of tantalium in the induction of osteogenesis.63,64 The marked porosity of tantalium provides this material with biomechanical properties that improve the stability of the bone-metal interphase and favors osteoinduction and neovascularization.64 But even though the initial clinical results seem promising, long term, comparative studies are needed to determine this procedures usefulness.65 Another technique with which there have been good results but that is still being studied is the transplantation of autologous bone marrow in the necrotic lesion of the femoral head. This procedure has shown promising results regarding safety and efficacy in the Reumatol Clin. 2007;3(2):78-84
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Figure 1. Tantalium rod in an osteonecrotic femoral head.
early stages of ON. Thus, a recent randomized study that included 13 patients with ON (18 hips) in stages I and II compared the effects of this procedure with forage and observed that, even if the majority of the hips (63%) included in the treatment group with forage worsened, ending in a stage III disease after 24 months of followup, only 10% of the group treated with a bone marrow transplant progressed to that stage.66 Other treatments, such as stimulation through electromagnetic fields have also been indicated for the treatment of this process, either as a primary therapy or as a coadjuvant associated with nucleus decompression and also with bone implant.67 This treatment could stimulate osteogenesis and neovascularization, but studies to confirm their effectiveness are needed68; in the same manner, treatment with extracorporeal shock waves have been effective in the clinical evolution of femoral head, early-stage ON, though long term studies to confirm these results are needed.69 No doubt an interesting aspect is the role that bisphosphonates could play in the treatment of this disease. Ibandronate, zoledronate, and alendronate3,70,71 have demonstrated effectiveness in the prevention of bone collapse associated to ON in various animal experimentation models when administered in early stages of disease. This effect has been attributed to a reduced bone remodeling produced that leads to a repair zone in the area of avascular necrosis and preserves the trabecular structure, therefore preventing bone collapse.3 It is important to remember that among the ethiopathogenic mechanisms implicated in osteonecrosis, there is also an increase in osteocytic apoptosis in patients treated with GC, something that is very interesting because bisphosphonates prevent osteocyte apoptosis.72,73 A recent prospective, uncontrolled study that included 60 patients 3 that were treated with alendronate (10 mg/day or 70 mg/week p.o.) for femoral ON with 82
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a 3 month to 5 year follow-up indicated that bisphosphonates are associated to reduced pain and radiographic progression that exempted most patients from an early surgical intervention. Also, a randomized study that included 40 patients with femoral head ON treated with alendronate (70 mg/week), with a followup of 24-28 months,74 showed less progression to bone collapse than in patients treated with alendronate in the control group (2/29 femoral heads in the group treated with alendronate and 19/25 in the control group). This data is certainly insufficient to indicate treatment with bisphosphonates in these patients, but it does point to a necessity in controlled studies in the long term that include a larger number of individuals and analyze these treatments. Lastly, for patients in an advanced stage of the disease with pain and associated functional limitation, total hip arthroplasty is the treatment of choice. But the results of this procedure in younger patients are less consistent, thus the majority of studies communicate a worse prognosis than in other diseases. A study that compared the evolution of hip arthroplasty in patients with ON and coxarthrosis indicated a much higher review rate in patients with ON (28% and 6%) with a shorter review time (5 years before patients with ON). The authors commented that it is possible that patients with ON have a worse quality of life and higher weight and, by virtue of being younger, more physical activity.75 This fact has led to the current consideration being made for resurfacing prosthesis of the femoral head in young patients.76 The treatment of ON continues to be a controversial subject and depends of several factors such as age, the stage of ON and symptoms. The development of new procedures and the potential of bisphosphonates open new perspectives in the therapeutic approach of this process.
Addendum Since the review of this article, new therapeutic approaches to ON have been published based on animal model experiments, such as the treatment with subcutaneous osteoprotegerin and the intraosseus of ibandronatein the ischemic femoral head. Both treatments have shown a reduction in femoral head deformity after ischemic ON. For more information on these experiments please consult the following references: Aya-ay J, Athavale S, Morgan-Bagley S, Bian H, Gauss F, Kim HKW. Retention, distribution, and effects of intraosseously administered ibandronate in the infracted femoral head. J Bone Miner Res. 2007;22:93-100. Kim HK, Morgan-Bagley S, Kostenuik P. RANKL inhibition: a novel strategy to decrease femoral head deformity alter ischemic osteonecrosis. J Bone Miner Res. 2006;21:1946-54.
Martínez-Ferrer MA et al. Osteonecrosis. What Is New?
References 1. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med. 1992;326:1473-9. 2. Mont MA, Hungerford DS. Current concepts review: nontraumatic avascular necrosis of the femoral head. J Bone Joint Surg. 1995;77-A:459-74. 3. Agarwala S, Jain D, Joshi VR, Sule A. Efficacy of alendronate, a biphosfonate, in the treatment of AVN of the hip. A prospective open-label study. Rheumatology. 2005;44:352-9. 4. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Sem Arthritis Rheum. 2002;32:94-124. 5. Calder JDF, Buttery L, Revell PA, Pearse M, Polak JM. Apoptosis– a significant cause of bone cell death in osteonecrosis of the femoral head. J Bone Joint Surg. 2004;86-B:1209-13. 6. Weinstein RS, Manolagas SC. Apoptosis and osteoporosis. Am J Med. 2000;108:153-64. 7. Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab. 2000;85:2907-12. 8. Gu G, Mulari M, Peng, Hentunene TA, Väänänen HK. Death of osteocytes turns off the inhibition of osteoclats and triggers local bone resorption. Biochem Biophys Res Com. 2005; 335;1095-101. 9. Liu YF, Chen WM, Lin YF, Yang RC, Lin MW, Li LH, et al. Type II collagen gene variants and inherited osteonecrosis in the femoral head. N Engl J Med. 2005;352:2294-301. 10. Zizic TM, Marcoux C, Hungerford DS, Dansereau JV, Stevens MB. Corticosteroid therapy associated with ischemic necrosis of bone in systemic lupus erythematosus. Am J Med. 1985;79:596-604. 11. Lieberman JR, Scaduto AA, Wellmeyer E. Symptomatic osteonecrosis of the hip after orthotopic liver transplantation. J Arthroplasty. 2000;15:76771. 12. Taillandier J, Alemanni M, Samuel D, Bismuth H. Rheumatic complications following liver transplantation. Transplant Proc. 1999;31:1717-8. 13. Bradbury G, Benjamin J, Thompson J, Klees E, Copeland J. Avascular necrosis of bone after cardiac transplantation. Prevalence and relationship to administration and dosage of steroids. J Bone Joint Surg. 1994;76-A:13858. 14. Schoch OD, Speich R, Schmid C, Tschopp O, Russi EW, Weder W, et al. Osteonecrosis after lung transplantation: cystic fibrosis as a potential risk factor. Transplantation. 2000;69:1629-32. 15. Marston SB, Gillingham K, Bailey RF, Cheng EY. Osteonecrosis of the femoral head after solid organ transplantation: a prospective study. J Bone Joint Surg. 2002;84-A:2145-51. 16. Nehme D, Rondeau E, Paillard F, Moreau JF, Nussaume O, Kanfer A, et al. Aseptic necrosis of bone following renal transplantation: relation with hyperparathyroidism. Nephrol Dial Transplant. 1989;4:123-8. 17. Ibels LS, Alfrey AC, Huffer WE, Weil R 3rd. Aseptic necrosis of bone following renal transplantation: experience in 194 transplant recipients and review of the literature. Medicine (Baltimore). 1978;57:25-45. 18. Metselaar HJ, van Steenberge EJ, Bijnen AB, Jeekel JJ, van Linge B, Weimar W. Incidence of osteonecrosis after renal transplantation. Acta Orthop Scand. 1985;56:413-5. 19. Sakai T, Sugano N, Kokado Y, Takahara S, Ohzono K, Yoshikawa H. Tacrolimus may be associated with lower osteonecrosis rates after renal transplantation. Clin Orthop Rel Res. 2003;415:163-70. 20. Antin JH. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med. 2002;347:36-42. 21. Schulte CM, Beelen DW. Avascular osteonecrosis after allogeneic hematopoietic stem-cell transplantation: diagnosis and gender matter. Transplantation. 2004;78:1055-63. 22. Tauchmanova L, de Rosa G, Serio B, Fazioli F, Mainolfi C, Lombardi G, et al. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and review. Cancer. 2003;97:2453-61. 23. Schulte CM, Beelen DW. Avascular osteonerosis after allogeneic hematopoietic stem-cell transplantation and gender matter. Transplantation. 2004;78:105563. 24. Mont MA, Glueck CJ, Pacheco IH, Wang P, Hungerford DS, Petri M. Risk factors for osteonecrosis in systemic lupus erythematosus. J Rheumatol. 1997;24:654-62. 25. Oinuma K, Harada Y, Nawata Y, Takabayashi K, Abe I, Kamikawa K, et al. Osteonecrosis in patients with systemic lupus erytematosus develops very early after starting high dose corticosteroid treatment. Ann Rheum Dis. 2001;60:1145-8. 26. Abeles M, Urman JD, Rotthfield NF. Aseptic necrosis of bone in systemic lupus erythematosus. Relatiopnship to corticosteroid therapy. Arch Intern Med. 1978;138:750-4.
27. Dimant J, Ginzler EM, Diamond HS, Schlesinger M, Marino CT, Weiner M, et al. Computer analysis of factors influencing the appearance of aseptic necrosis in patients with SLE. J Rheumatol. 1978;5:136-41. 28. Sugano N, Ohzono K, Mashuara K, Takaoka K, Ono K. Prognostication of osteonecrosis of the femoral head in patients with systemic lupus erythematosus by magnetic resonance imaging. Clin Orthop. 1994;305: 190-9. 29. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erytematous: is there a role for antiphospholipid antibodies? Ann Rheum Dis. 2000;59:462-7. 30. Laroche M, Ludot I, Thiechart M, Viguier G, Dromer C, Mazieres B. Histological appearance of the intra-osseous vessels of the femoral head in aseptic osteonecrosis of the hip, with or without antiphospholipid antibodies. Clin Rheumatol. 1997;16:367-71. 31. Migliaresi S, Picillo U, Ambrosone L, di Palma G, Mallozzi M, Tesone ER, et al. Avascular osteonecrosis in patients with SLE: relation to corticosteroid therapy and anticardiolipin antibodies. Lupus. 1994;3:37-41. 32. Nagasawa K, Ishii Y, Mayumi T, Tada Y, Ueda A, Yamauchi Y, et al. Avascular necrosis of bone in systemic lupus erithematosus: possible role of haemostathic abnormalities. Ann Rheum Dis. 1989;48:672-6. 33. Mok CC, Lau CS, Wong RWS. Risk factors for avascular necrosis in systemic lupus eritematosus. Br J Rheumatol. 1998;37:895-900. 34. Asherson RA, Liote F, Page B, Meyer O, Buchanan N, Khamashta MA, et al. Avascular necrosis of bone and antiphospholipid antibodies in systemic lupus erytematosus. J Rheumatol. 1993;20:284-8. 35. Tektonidou MG, Malagari K, Vlachoyiannopoulos PG, Kelekis DA, Moutsopoulos HM. Assymptomatic vascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis Rheum. 2003; 48:732-6. 36. Lee JS, Koo KH, Ha YC, Koh KK, Kim SJ, Song HR, et al. Role of thrombotic and fibrinolytic disorders in osteonecrosis of the femoral head. Clin Orthop. 2003;417:207-16. 37. Jones JP. Epidemiological risk factors for non-traumatic osteonecrosis. Orthopeade. 2000;29:370-9. 38. Egan RM, Munn RK. Catastrophic antiphospholipid antibody syndrome presenting with multiple thromboses and sites of avascular necrosis. J Rheumatol. 1994;21:2376-9. 39. Yoo WH. Multiple rib infarcts: a rare form of osteonecrosis in antiphospholipid syndrome. Ann Rheum Dis. 2004;63:457-8. 40. Mundo J, Peris P, Monegal A, Navasa M, Cervera R, Guañabens N. Multifocal avascular necrosis after liver transplantation: an unusual presentation of the antiphospholipid síndrome. Lupus. 2006;15:304-7. 41. Zalavras CG, Vartholomatos G, Dokou E, Malizos KN. Factor V Leiden and prothrombin gene mutations in femoral head osteonecrosis. Thromb Haemost. 2002;87:1079-80. 42. Arruda VR, Belangero WD, Ozelo MC, Oliveira GB, Pagnano RG, Volpon JB, et al. Inherited risk factors for thrombofilia among children with LeggCalve-Perthes disease. J Pediatr Orthop. 1999;19:84-7. 43. Jones LC, Mont MA, Le TB, Petri M, Hungerford DS, Wang P, et al. Procoagulants and osteonecrosis. J Rheumatol. 2003;30:783-91. 44. Miller KD, Masur H, Jones EC, Joe GO, Rick ME, Kelly GG, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med. 2002;137:17-25. 45. Brown P, Crane L. Avascular necrosis of bone in patients with human immunodeficiency virus infection: report of 6 cases and review of the literature. Clin Infect Dis. 2001;32:1221-6. 46. Glebsy MJ, Hoover DR, Vaamonde CM. Osteonecrosis in patients infected with human immunodeficiency virus: a case-control study. J Infect Dis. 2001;184:519-23. 47. Gutiérrez F, Padilla S, Ortega E, García JA, Flores J, Galera C, et al. Avascular necrosis of the bone in HIV-infected patients: incidence and associated factors. AIDS. 2002;16:481-3. 48. Ficat RP, Arlet J. Functional investigation of bone under normal conditions. In: Hungerford DS, editor. Ischemia and necrosis of bone. Baltimore: Williams & Wilkins; 1980. p. 29-52. 49. Gardeniers JW. A new international classification of osteonecrosis of the ARCO-committee on terminology and classification. ARCO News. 1992;4:41-6. 50. Mont MA, Carbone JJ, Faibank AC. Core decompression versus nonoperative management for osteonecrosis of the hip. Clin Orthop. 1996;324: 169-78. 51. Stulberg BN, Davis AW, Bauer TW, Levine M, Easley K. Osteonecrosis of the femoral head. A prospective randomized treatment protocol. Clin Orthop Relat Res. 1991;268:140-51. 52. Koo KH, Kim R, Ko GH, Song HR, Jeong ST, Cho SH. Preventing collapse in early osteonecrosis of the femoral head. A randomised clinical trial of core decompression. J Bone Joint Surg. 1995;77-B:870-4. 53. Castro Jr FP, Barrack RL. Core decompression and conservative treatment for avascular necrosis of the femoral head: a meta-analysis. Am J Orthop. 2000;29:187-94.
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54. Yoon TR, Song EK, Rowe SM, Park CH. Failure after core decompression in osteonecrosis of the femoral head. Int Orthop. 2001;24: 316-8. 55. Lavernia CJ, Sierra RJ. Core decompression in atraumatic osteonecrosis of the hip. J Arthroplasty. 2000;15:171-8. 56. Lieberman JR, Conduah A, Urist MR. Treatment of osteonecrosis of the femoral head with core decompression and human bone morphogenetic protein. Clin Orthop Rel Res. 2004;429:139-45. 57. Lieberman JR. Core decompression for osteonecosis of the hip. Clin Orthop Rel Res. 2004;418:29-33. 58. Sugioka Y, Katusi I, Hotokebuchi T. Transtrocanteric rotational osteotomy of the femoral head for the treatment of osteonecrosis. Follow-up statistics. Clin Orthop. 1982;169:115-26. 59. Marcus ND, Enneking WF, Massan RA. The silent hip in idiopathic aseptic necrosis. Treatment by bone-grafting. J Bone Joint Surg. 1973;55 A:135166. 60. Rijnen WH, Gardeniers JW, Buma P, Yamano K, Slooff TJ, Schreurs BW. Treatment of femoral head osteonecrosis using bone impaction grafting. Clin Orthop Relat Res. 2003;417:74-83. 61. Urbaniak JR, Harvey EJ. Revascularization of the femoral head in osteonecrosis. J An Acad Orthop Surg. 1998;6:44-54. 62. Marciniak D, Furey C, Shaffer JW. Osteonecrosis of the femoral head. A study of 101 hips treated with vascularizated fibular grafting. J Bone Joint Surg. 2005;87-A:742-7. 63. Bobin JD, Stackpool GJ, Hacking SA, Tanzer M, Krygier JJ. Characteristics of bone ingrowth and interface mechanics of bone ingrowth and interface mechanics of new porous tantalum biomaterial. J Bone Joint Surg. 1999;81B:907-14. 64. Bobyn JD, Poggie RA, Krygier JJ, Lewallen DG, Hanssen AD, Lewis RJ, et al. Clinical validation of structural porous tantalum biomaterial for adult reconstruction. J Bone Joint Surg. 2004;86-A:123-9. 65. Tsao AK, Roberson JR, Christie MJ, Dore DD, Heck DA, Robertson DD, et al. Biomechanical and clinical evalutions of a porous tantalum implant for the treatment of early-stage osteonecrosis. J Bone Joint Surg. 2005;87-A: 22-7.
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66. Gangji V, Hauzeur JP. Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. Bone Joint Surg. 2005;87A:106-12. 67. Mazières B. Osteonecrosis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology. 3rd ed. Edinburg: Mosby; 2003. p. 1877-90. 68. Rizzo M, Urbaniak JR. Osteonecrosis. In: Harris Jr EDH, Budd RC, Firestein GS, Genovese MC, Sergent JS, Ruddy S, et al, editors. Kelley´s text book of Rheumatology. 7th ed. Philadelphia: Elsevier-Saunders; 2005. p. 181228. 69. Wang CJ, Wang FS, Huang CC, Yang KD, Weng LH, Huang HY. Tretament for osteonecrosis of the femoral head: Comparison of extracorporeal shock waves with core decompression and bone-grafting. J Bone Joint Surg. 2005;87-A:2380-7. 70. Kim H, Randal TS, Bian H, Jenkins J, Garces A, Bauss F. Ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoral epiphysis in immature pigs. J Bone Joint Surg. 2005;87-A:550-7. 71. Little DG, Peat RA, Mcevoy A, Williams PR, Smith EJ, Baldock PA. Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats. J Bone Miner Res. 2003;18:2016-22. 72. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999;104:1363-74. 73. Kogianni G, Mann V, Ebetino F, Nuttall M, Nijweide P, Simpson H, et al. Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci. 2004;75:2879-95. 74. Lai KA, Shen WJ, Yang CY, Shao CJ, Hsu JT, Lin RM. The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. J Bone Joint Surg. 2005;87-A:2155-9. 75. Saito S, Saito M, Nishia T, Ohzono K, Ono K. Long-term results of total hip arthroplasty for osteonecrosis of the femoral head. A comparison with osteoarthritis. Clin Orthop Relat Res. 1989;244:198-207. 76. Schmalzried TP. Total resurfacing for osteonecrosis of the hip. Clin Orthop Relat Res. 2004;429:151-6
Osteonecrosis. What Is New? M. Ángeles Martínez-Ferrer, Pilar Peris, and Núria Guañabens Servicio de Reumatología, Hospital Clínic, Barcelona, Spain
Osteonecrosis, also known as aseptic necrosis, is a pathological process that has been associated with numerous conditions. The pathogenesis of osteonecrosis and especially the treatment both remain an area of controversy. In this article we review the etiology and pathogenesis of osteonecrosis as well as the main therapeutic options.
head is the zone most frequently affected and the one in which there is the most experience regarding evolution and treatment; therefore, in this article, we will be referring especially to that localization.
Key words: Osteonecrosis. Avascular necrosis. Aseptic
Thought he true incidence of this process is not known, it is estimated that approximately 15 000 new cases present themselves each year in the United States, constituting 10% of the yearly 500 000 arthroplasties done every year in that country, with a male:female ratio of 8:1.1 Because non-traumatic hip ON in its early stages is frequently asymptomatic, it is difficult to establish the natural history of this process. In spite of that, 68%80% of patients with asymptomatic hip ON without treatment progress to the final stages of ON in 3 to 5 years, without any relationship to etiology and the time of evolution to collapse. 31%-35% will have a satisfactory evolution without surgery2; nonetheless, up to 50% of the cases require arthroplasty at 3 years since diagnosis and between 30%-70% of cases has bilateral affection of the hips.3 Advance stages at the moment of diagnosis, the extension of the lesion (>50% of the femoral head) and its localization (anterolateral zone of the femoral head) are poor prognostic factors. The femoral head is the most frequent localization, but other sites can be affected also, among which the humeral head, the condyle of the femur, the proximal tibia and the carpal and tarsal bones deserve mention. Around 3% of patients present multifocal ON.1
necrosis. Ischemic necrosis.
Osteonecrosis. ¿Qué hay de nuevo? La osteonecrosis, también conocida como necrosis avascular, se ha asociado a numerosos procesos. Su patogenia y, especialmente, su tratamiento son motivo de controversia. En este artículo se revisan la etiología y la patogenia de la osteonecrosis y sus principales opciones terapéuticas. Palabras clave: Osteonecrosis. Necrosis avascular.
Necrosis aséptica. Necrosis isquémica.
Osteonecrosis (ON), also known as avascular necrosis or aseptic necrosis, is a disease that has been related to multiple processes. Though in many cases the mechanisms that lead to ON are not completely clear, in others a deterioration of the vascularization of bone that produces necrosis of the bone tissue has been identified. It is a progressive process that can lead to fragmentation and sinking of the bone structure and to joint destruction secondarily, in a period of 3 to 5 years. Because ON affects mainly young adults between 20 and 40 years of age, its consequences are a real public health problem. The most frequent localization is the epiphysis and, although any part of the skeleton is liable to undergo ON, the femoral
Correspondence: Dra. M.A. Martínez-Ferrer. Servicio de Reumatología. Hospital Clínic. Villarroel, 170. 08036 Barcelona. España. E-mail: [email protected] Manuscript received January 18, 2006; accepted for publication June 7, 2006.
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Epidemiology and Evolution
Etiology Several causes associated to the development of ON have been described. In some, such as in proximal femur fracture, sickle cell anemia, or decompression illness, the cause seems evident, while in others, such as treatment with glucocorticoids (GC) or alcohol consumption, the cause is not so clear. The common denominator is the femoral head liability to ischemia, but the pathogenic mechanism is variable. In the case of a femoral fracture, compression or rupture of a blood vessel is the cause of ON, while in sickle cell anemia and in decompression illness, it is attributed to alterations in sinusoidal circulation. Several pathogenic mechanisms have been
Martínez-Ferrer MA et al. Osteonecrosis. What Is New?
proposed in relation to the rest of the ON, such as vascular alterations secondary to atherosclerosis, coagulation defects, repeated microfractures, fat embolism, adypocyte hypertrophy, among others. For example, with respect to GC it has been described that the alterations in the metabolism of lipids associated to this treatment would favor the development of fat embolisms that would lead to micro vessel obstruction or would produce an increase in bone marrow fat that would lead to vascular insufficiency due to compression, leading to the development of ON. On the other hand, treatment with GC has also been associated to an increment in the production of endothelium vasoconstrictive substances such as endothelin 1, which could lower the tissue perfusion and favor the appearance of this complication.4 Thrombophilia and hypofibrinolysis have also been implicated in the development of ON in some cases, causing intravascular coagulation in the bone tissue microcirculation that leads to venous or arterial thrombosis.4 Osteocyte and osteoblast apoptosis has been pointed out in the past few years as an important probable ethiopathogenic mechanism in this disease, concretely in relationship to ON due to GC and alcohol, signaling that it may be mediated, at least partially, by an increase in the local production of nitric oxide.5 In patients with ON due to GC, an abundance of apoptotic osteocytes that affect the adjacent lining cells in the area of bone collapse have been observed. It has been proposed that this fact would lead to further bone collapse.6,7 Therefore, osteocyte apoptosis seems to play a fundamental role in the local activation of osteoclasts to initiate bone resorption.8 There has been several cases described recently of familial dominant autosomic ON linked to mutations in the collagen type II (COL2A1) gene.9 Though this mutation constitutes an infrequent cause of ON, because it has not been observed in patients with idiopathic ON without a family history, it implicates the functional alterations of type II collagen in the development of some cases of ON.
Frequent Causes of Osteonecrosis Besides posttraumatic ON, be it due to femoral neck fracture (especially the sub capital fractures) or hip luxation (especially if reduction is performed late rather than early), treatment with GC is one of the most common causes of ON. Between 3% and 25% of patients using GC develop ON,1 with a dose dependent risk. In this sense, the use of moderate doses of GC (<15-20 mg/day) are associated with a low risk of ON (<3%), while larger doses used for longer periods of time confer a higher risk.10 Nonetheless, one must remember that these patients frequently have multiple associated risk factors that can lead to the development of this process. Some studies indicate that 100% of the cases of ON associated to GC treatment had continued treatment with prednisone in excess of 20
mg/day.10 There is evident that points out that the initial dose of GC can be as important as the total dose and the duration of treatment. In transplant patients, the development of ON is a relatively frequent complication, with prevalence oscillating between 2% and 24% and depends on the dose employed and the transplanted organ.11 The incidence of ON tends to be lower, in the order of 2%-3%, after liver or heart transplant than after lung or kidney transplant, where incidence is around 10% and 34%.14,15 In these patients, a history of osteopenia and hyperparathyroidism are risk factors that have been associated to the risk of ON.16 Frequently ON in renal transplant patients can affect more than one localization (50%-70% of cases).17,18 Nonetheless, its incidence has lowered since the introduction of new immunosupressants such as tacrolimus, allowing for a reduction in the dose of GC.19 Bone marrow transplant (BMT) has also been associated to this complication, especially allogenic BMT, with a frequency around 5%20,21; graft-versus-host disease and the cumulative dose of GC are risk factors related to the development of ON in these patients.22 But other factors such as the type of hematologic disease and the gender, both of the patient and the donor, have also been related to this complication. Thus the patients with acute lymphoblastic leukemia and women who have received a transplant from another woman, present ON with a greater frequency.23 In other diseases such as systemic lupus erythematosus (SLE), the development of ON has been observed in 4% of patients24,25; but if treatment with GC, especially at a dose >20 mg/day, constitutes one of the main risk factors for the development of ON in these patients,26-28 dyslipidemia, and antiphospholipid antibodies are other factors relating to the development of ON in this process.29 Though the role of antiphospholipid antibodies in the development of ON in patients with SLE is controverted,3034 their relationship with the development of ON in patients with primary antiphospholipid síndrome seems evident. Thus, it has been recently shown that 20% of these patients develop ON.35 Some studies, though not all, have also observed an increment in the incidence of antiphospholipid antibodies in patients with ON.29,36,37 Isolated cases of patients with multifocal ON and associated antiphospholipid antibodies have been described.38-40 Other isolated studies implicate alterations in other coagulation factors with relation to the development of ON, such as the presence of a mutation in the factor V Leiden gene41,42 or the inhibition of plasminogen activation factor.43 The excessive consumption of alcohol is also a frequent cause of ON. Even though the mechanism by which this complication is produced in these patients, several ethiopathogenic mechanisms have been proposed in relation to the development of ON in this process, such as fat embolus, venous stasis or the increase in the concentrations of cortisol, among others. The Reumatol Clin. 2007;3(2):78-84
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development of ON is frequent in other diseases such as sickle cell anemia, in which up to 50% of patients can present the complication, and in Gauchers´ disease, a metabolic entity in which approximately 60% of patients develop ON. Lastly, human immunodeficiency virus (HIV), independent of the degree of immune system compromise, can produce an increment in the risk of ON; in these patients a prevalence of up to 4% has been noted, occasionally presenting as multifocal ON. Factors such as dyslipidemia secondary to the treatment of protease inhibitors, GC treatment, hypolipemics or testosterone could be related to its development.44 The role that the complications linked to HIV, mainly coagulation disorders (antiphospholipid antibodies or S protein deficit) and vasculitis have been a motive of discussion but their participation has not been able to be confirmed. It is probable that in these patients the development of ON is multifactorial.45,46 A recent study that analyzes the factors related to ON in patients with HIV indicate that the majority of patients (86%) had at least one known risk factor for this complication.47
cuts. Bone scanning is a less sensitive and specific technique than RM in early stages, though it is useful in the diagnosis of multifocal illness. Another imaging technique is computed tomography (CT) that can be useful in the detection of an occult subchondral fracture, but is less sensitive in the early diagnosis of ON (stage I). As with MR, CT is not necessary for the diagnosis of ON in late stages of disease because diagnosis with simple x-rays is easy.
Classification and Staging of Osteonecrosis Several staging indexes for ON based on the degree of x-ray affection, histological damage, and clinical symptoms have been proposed. The classification of Ficat et al48 stands out among them, basing itself on the x-ray findings and has been used extensively (Table 1), as does the index of the Association for the Research of Circulation of the Bone (ARCO), 49 that unifies the results of several classifications (Table 2). The latter is difficult to apply in daily practice and is mainly employed in research studies.
Diagnosis Treatment Upon suspicion of ON, a simple x-ray study must be carried out. When the x-ray is normal and there is a clinically based suspicion of ON, the imaging method of choice is magnetic resonance (MR). At the beginning of symptoms, the radiological studies tend to be normal; the first findings are changers in the bone mineral density followed by sclerosis and the appearance of cysts as the disease progresses. The pathognomonic sign is the “halfmoon” image, indicating subchondral collapse. In advance stages of the disease there is an objective loss of sphericity of the femoral head and a narrowing of the joint space as well as degenerative changes of the acetabulum. Both hips should always be x-rayed to evaluate bilateral affection. MR constitutes the most sensitive technique for diagnosis of ON and allows for its diagnosis in early stages of disease. The study must include imaging in T1 and T2 with coronal and sagital
A controversial topic in ON is, without a doubt, its therapeutic approach. Thus, in many occasions, conservative treatment is indicated for this process, including joint rest and analgesia. Nonetheless, this type of treatment does not seem to modify the natural evolution of ON nor prevent bone collapse, because with this kind of treatment, only 23% of hips present a good clinical result after a mean follow up of 34 months.50 Central decompression by single or multiple perforations (forage) through the femoral neck is another kind of treatment that has frequently been used. It a surgical procedure in which several perforations of a small caliber or a larger one are done attaining decompression at the same time the necrotic bone tissue is removed. When the intraosseus pressure diminishes, pain is relieved and, theoretically, revascularization of the necrotic tissue
TABLE 1. ON Classification According to Ficat et al48 Stage 0
Diagnosis techniques are normal and patient is asymptomatic
Stage 1
Normal x-ray, asymptomatic or, mild symptoms, bone scan shows a cold spot on the femoral head and biopsy is positive
Stage 2
x-ray changes, mild symptoms, and increased uptake on bone scan. According to x-ray affection it can be classified into A or B
Stage 3
x-ray changes, loss of sphericity and collapse, mild to moderate symptoms, increase in bone uptake
Stage 4
x-ray changes, joint space narrowing and acetabulum changes, moderate to severe symptoms and increased uptake in bone scan
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TABLE 2. Osteonecrosis Classification According to ARCO49,* Stage 0
The diagnostic tests are normal, patients are asymptomatic, diagnosis is histological
Stage 1
Normal x-ray and CT, MR and biopsy are negative. According to the extension of the lesion it is subclassified in: A: <15% B: 15%-30% C: >30%
Stage 2
Radiographic changes without collapse. According to the degree of affection it is sub classified in A, B, or C
Stage 3
“Half moon” sign is characteristic; indicating collapse. MR or CT can be necessary for diagnosis. The extension of the lesion is sub classified in A, B, or C
Stage 4
There is a flattening of the femoral head with joint space narrowing and early signs of arthrosis. Collapse usually occurs in the anterolateral or superior loading area. The best technique to observe collapse is CT. This stage can be subdivided in: A: extension of the collapse <15% and 2 mm depression B: collapse 15%-30%, depression 2-4 mm C: collapse >30%, depression >4 mm
Stage 5
All of the abovementioned radiographic changes and a narrowing of the joint space. Collapse secondary to arthrosis, sclerosis, cysts, and marginal osteophytes
Stage 6
Extensive destruction of the femoral head
*MR indicates magnetic resonance; CT, computerized tomography.
occurs. In the last few years there have been numerous studies attempting to evaluate the efficacy of this technique.51 For example, in a randomized study that compared the efficacy of this technique versus conservative treatment the results showed that, even if there were significant differences in favor of treatment with decompression in relation to the improvement of pain, no differences were observed regarding radiographic evolution,52 while a meta-analysis comparing the efficacy of both procedures indicated that the forage could only be useful in the treatment of stage I hip ON53; therefore this type of treatment is indicated in patients presenting early stages of disease and limited extension lesions.54,55 Recently it has been pointed out that additional treatment with local growth factors such as morphogenetic protein could improve this treatments efficacy. 56,57 Another surgical procedure cited frequently is femoral neck osteotomy, consisting in the modification of the loading axis on the femoral head. This procedure would facilitate recovery by modifying the load over the necrotic lesion. But the results of clinical trials are variable and, curiously, the best results are observed in Japanese populations where, after a follow up period of 2-9 years, patients show excellent results of up to 90%.58 This procedure is currently being abandoned. There are other techniques that also imply a surgical approach of the bone lesion, such as the cortical-spongy bone implant and the revascularized bone implant. In the former a cortical or spongy bone implant (autologous or allogenic) is introduced through the decompression zone into the necrotic area after debridement. The bone implant offers structural support for the subchondral bone, theoretically preventing bone collapse. Marcus et al59 described the results of this technique in a group of
48 patients with different stages of affection (I-IV). Therefore, while 64% of the patients in stages I and II presented a good evolution with this type of treatment, no patient I stages III and IV had satisfactory results. Another technique that has been employed is the impacted bone implant, with interesting results in extensive ON. 60 On the other hand, the implant of vascularized free or pediculated bone consists in the implantation of cortical or spongy bone tissue with its vascular appendage (usually free peroneus through microsurgery) to the interior of the femoral neck through a decompression tract. The results described with this type of implant are better.61 In a study that included 101 hips (in all stages of ON) from 86 patients and with a minimum follow-up of 5 years, there was a hip survival of 61% at 5 years.62 It must be said that a recent technique has been applied to this disease, the implantation of a tantalium rod or screw, that consists in the collocation of a porous bar made tantalium in the interior of the femoral neck (Figure); its indication is based on the fact that it will serve as mechanical support and the intrinsic properties of tantalium in the induction of osteogenesis.63,64 The marked porosity of tantalium provides this material with biomechanical properties that improve the stability of the bone-metal interphase and favors osteoinduction and neovascularization.64 But even though the initial clinical results seem promising, long term, comparative studies are needed to determine this procedures usefulness.65 Another technique with which there have been good results but that is still being studied is the transplantation of autologous bone marrow in the necrotic lesion of the femoral head. This procedure has shown promising results regarding safety and efficacy in the Reumatol Clin. 2007;3(2):78-84
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Figure 1. Tantalium rod in an osteonecrotic femoral head.
early stages of ON. Thus, a recent randomized study that included 13 patients with ON (18 hips) in stages I and II compared the effects of this procedure with forage and observed that, even if the majority of the hips (63%) included in the treatment group with forage worsened, ending in a stage III disease after 24 months of followup, only 10% of the group treated with a bone marrow transplant progressed to that stage.66 Other treatments, such as stimulation through electromagnetic fields have also been indicated for the treatment of this process, either as a primary therapy or as a coadjuvant associated with nucleus decompression and also with bone implant.67 This treatment could stimulate osteogenesis and neovascularization, but studies to confirm their effectiveness are needed68; in the same manner, treatment with extracorporeal shock waves have been effective in the clinical evolution of femoral head, early-stage ON, though long term studies to confirm these results are needed.69 No doubt an interesting aspect is the role that bisphosphonates could play in the treatment of this disease. Ibandronate, zoledronate, and alendronate3,70,71 have demonstrated effectiveness in the prevention of bone collapse associated to ON in various animal experimentation models when administered in early stages of disease. This effect has been attributed to a reduced bone remodeling produced that leads to a repair zone in the area of avascular necrosis and preserves the trabecular structure, therefore preventing bone collapse.3 It is important to remember that among the ethiopathogenic mechanisms implicated in osteonecrosis, there is also an increase in osteocytic apoptosis in patients treated with GC, something that is very interesting because bisphosphonates prevent osteocyte apoptosis.72,73 A recent prospective, uncontrolled study that included 60 patients 3 that were treated with alendronate (10 mg/day or 70 mg/week p.o.) for femoral ON with 82
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a 3 month to 5 year follow-up indicated that bisphosphonates are associated to reduced pain and radiographic progression that exempted most patients from an early surgical intervention. Also, a randomized study that included 40 patients with femoral head ON treated with alendronate (70 mg/week), with a followup of 24-28 months,74 showed less progression to bone collapse than in patients treated with alendronate in the control group (2/29 femoral heads in the group treated with alendronate and 19/25 in the control group). This data is certainly insufficient to indicate treatment with bisphosphonates in these patients, but it does point to a necessity in controlled studies in the long term that include a larger number of individuals and analyze these treatments. Lastly, for patients in an advanced stage of the disease with pain and associated functional limitation, total hip arthroplasty is the treatment of choice. But the results of this procedure in younger patients are less consistent, thus the majority of studies communicate a worse prognosis than in other diseases. A study that compared the evolution of hip arthroplasty in patients with ON and coxarthrosis indicated a much higher review rate in patients with ON (28% and 6%) with a shorter review time (5 years before patients with ON). The authors commented that it is possible that patients with ON have a worse quality of life and higher weight and, by virtue of being younger, more physical activity.75 This fact has led to the current consideration being made for resurfacing prosthesis of the femoral head in young patients.76 The treatment of ON continues to be a controversial subject and depends of several factors such as age, the stage of ON and symptoms. The development of new procedures and the potential of bisphosphonates open new perspectives in the therapeutic approach of this process.
Addendum Since the review of this article, new therapeutic approaches to ON have been published based on animal model experiments, such as the treatment with subcutaneous osteoprotegerin and the intraosseus of ibandronatein the ischemic femoral head. Both treatments have shown a reduction in femoral head deformity after ischemic ON. For more information on these experiments please consult the following references: Aya-ay J, Athavale S, Morgan-Bagley S, Bian H, Gauss F, Kim HKW. Retention, distribution, and effects of intraosseously administered ibandronate in the infracted femoral head. J Bone Miner Res. 2007;22:93-100. Kim HK, Morgan-Bagley S, Kostenuik P. RANKL inhibition: a novel strategy to decrease femoral head deformity alter ischemic osteonecrosis. J Bone Miner Res. 2006;21:1946-54.
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